NEW YORK & SOUTH SAN FRANCISCO, Calif.—Back in 2014, Bristol-Myers Squibb and CytomX Therapeutics formed an alliance in the oncology arena based on the promise of CytomX’s Probody therapeutic platform and its potential to target tumors while sparing healthy tissues—and perhaps diseases apart from cancer as well. That deal came with $50 million up front for CytomX and a total deal value of as much as $1.6 billion if all milestones are met and all products go to market.

Now comes news that the two companies have expanded that deal to includes up to eight additional targets in oncology and other therapeutic areas using CytomX’s proprietary Probody platform. The new deal comes with $200 million up front, research funding and nearly $450 million in potential milestones for each target, plus tiered royalties, which means the deal could be worth $3.6 billion ultimately if all goes perfectly.

As the companies note, “Probody therapeutics are designed to take advantage of unique conditions in the tumor microenvironment to enhance the tumor-targeting features of an antibody and reduce drug activity in healthy tissues.” Theoretically, the Probody therapeutics remain inactive until they are activated by proteases in the tumor microenvironment, then they bind selectively to cells within tumor tissue. This can improve treatment by reducing off-target effects but also can possibly create a therapeutic window where one might not have otherwise existed. Because of the protease connection, Probody therapeutics may also have application in diseases other than cancer where proteases are dysregulated in affected tissues.

As part of the original collaboration signed in May 2014 to discover, develop and commercialize Probody therapeutics, Bristol-Myers Squibb has already selected four oncology targets, including CTLA-4. In the collaboration to date, Bristol-Myers Squibb has progressed the CTLA-4 Probody therapeutic to Investigational New Drug-enabling studies and the three other programs are in the lead discovery and optimization phase.

It was just recently, on Dec. 5, that CytomX announced the selection of a fourth target in the original 2014 deal by Bristol-Myers Squibb, which came with a $15-million milestone payment and represented the final target selection under this agreement.

“We are thrilled with the continued progress in our alliance with Bristol-Myers Squibb that has included two new target selections this year and the recent presentations of strong preclinical proof-of-concept data for our anti-CTLA-4 Probody therapeutic program at the European Society for Medical Oncology Symposium on Immuno-Oncology and the Society for Immunotherapy in Cancer Annual Meeting,” said Dr. Sean McCarthy, president and CEO of CytomX, when that late-2016 news was announced. “We look forward to continued progress in each of these collaboration programs as we pursue our vision of transforming lives with safer, more effective therapies.”

“CytomX’s Probody platform has enhanced our discovery research as we seek to direct the therapeutic effects of immunotherapy in a more targeted approach against tumors,” said Dr. Carl Decicco, head of discovery for Bristol-Myers Squibb, of the new, expanded deal. “We look forward to working more extensively with CytomX on this innovative and potentially disruptive approach in oncology as well as other disease areas.”

“This expanded collaboration with Bristol-Myers Squibb gives CytomX the opportunity to further the reach of our potentially transformational Probody technology and provides us with additional financial and strategic flexibility to build our company,” noted McCarthy. “With CX-072 in Phase 1/2, and CX-2009 approaching clinical studies, our broad wholly-owned pipeline is poised for initial proof of concept as we aim to reinvent therapeutic antibodies.”

Under the terms of the agreement, CytomX will grant Bristol-Myers Squibb exclusive worldwide rights to develop and commercialize Probody therapeutics for up to six additional oncology targets and two non-oncology targets. Bristol-Myers Squibb will make an upfront payment of $200 million to CytomX and, in addition, will provide research funding over the course of the research term. CytomX will also be eligible to receive up to $448 million in future development, regulatory and sales milestone payments for each collaboration target, as well as tiered royalties from the mid-single digits to low-double digits on net sales of each product commercialized by Bristol-Myers Squibb.